1. Field of the Invention
The present invention relates to molecular weight-enlarged ligands for catalysts for the asymmetric, homogeneous hydrogenation of double bonds.
2. Discussion of the Background
Catalytically active species for asymmetric, homogenous hydrogenation of double bonds are extremely advantageous for the industrial synthesis of organic substances. This is particularly the case due to their improved recyclability, which helps keep manufacturing costs low.
Molecular weight-enlarged catalysts for homogeneous enantioselective hydrogenation have been previously disclosed. J. Am. Chem. Soc. 1998, 120, 9481 et seq. addresses the problem of producing soluble molecular weight enlargements, inter alia for hydrogenation catalysts. Wandrey et al. have also reported the use of a molecular weight-enlarged hydrogenation catalyst in a membrane reactor (Angew. Chem. 1990, 102, 445 et seq.). U.S. Pat. No. 5,777,062 describes homogeneously soluble polymer-enlarged ligands for hydrogenation catalysts. The monomeric ligands are bound in that case to the polymer backbone through urethane or urea linkers.
The problems associated with the use of such catalysts have not been previously adequately resolved. Accordingly, there is still a need for novel catalyst systems which make it possible to perform continuous processes catalytically. The problems that must be addressed relate, for example, to the separability of the product from the catalyst with regard to the membrane used and to inactivation of the catalyst over time.
Accordingly, one object of the present invention is to provide a homogenous soluble hydrogenation catalyst that is readily separable from the product of hydrogenation.
A further object of the present invention is to provide a homogenous soluble hydrogenation catalyst having improved lifetime.
A further object of the present invention is to provide a molecular weight increased ligand for preparing such a hydrogenation catalyst.
Another object of the present invention is to provide a method for the production of such ligands and catalysts.
Another object of the present invention is to provide a method for asymmetric, homogenous hydrogenation of double bond containing compounds using the catalysts.
These and other objects of the present invention have been satisfied by the discovery of a ligand comprising a molecular weight-enlarged, homogeneously soluble ligand having an average molecular weight in the range from 1,000-1,000,000 g/mol comprising a molecular weight enlarging polymer and one or more ligands, wherein said one or more ligands are homochiral active centers of bis(3,4-diarylphosphinyl)pyrrolidine, wherein said one or more ligands are bound to said molecular weight enlarging polymer via a linker selected from the group consisting of formulae a)-g)
wherein
R represents H, (C1-C8) alkyl, (C6-C18) aryl, (C7-C19) aralkyl, or ((C1-C8) alkyl)1-3-(C6-C18) aryl;
X represents (C6-C18) arylene, (C1-C8) alkylene, (C1-C8) alkenylene, ((C1-C8) alkyl)1-3-(C6-C18) arylene, or (C7-C19) aralkylene;
Z represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein Z is further bound directly to said molecular weight enlarging polymer; and
W represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein W is further bound directly to said ligand;
or said one or more ligands are bound directly to said molecular weight-enlarging polymer, its use in preparing a catalyst and the catalyst prepared thereby, as well as the use of the catalyst in a method for the production of enantimerically enriched organic compounds.
The present invention relates to a molecular weight-enlarged, homogeneously soluble ligand having an average molecular weight of 1,000-1,000,000 g/mol which comprises a molecular weight enlarging polymer and one or more ligands, wherein the one or more ligands are homochiral active centers of bis(3,4-diarylphosphinyl)pyrrolidines, wherein these ligands are bound to said polymer via a linker selected from the group consisting of formulae a)-g):
wherein
R is H, (C1-C8) alkyl, (C6-C18) aryl, (C7-C19) aralkyl, ((C1-C8) alkyl)1-3-(C6-C18) aryl,
X is (C6-C18) arylene, (C1-C8) alkylene, (C1-C8) alkenylene, ((C1-C8) alkyl)1-3-(C6-C18) arylene, (C7-C19) aralkylene,
Z represents on the polymer side C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR,
W represents on the ligand side C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR,
or the active centers are bound directly to the molecular weight-enlarging polymer, and to the polymer-enlarged hydrogenation catalysts formed using these ligands. These catalysts are useful in industrial organic synthesis, and are very readily recyclable.
For the purposes of the present invention, the molecular weight enlarging polymer can be freely selected. The enlargement is limited, on the one hand, by considerations of practicability and cost and, on the other, by technical issues (retention capacity, solubility etc.). Some molecular weight enlarging polymers for catalysts are described in Reetz et al., Angew. Chem. 1997, 109, 1559 et seq.; Seebach et al., Helv. Chim Acta 1996, 79, 1710 et seq.; Kragl et al., Angew. Chem. 1996, 108, 684 et seq.; Schurig et al., Chem. Ber./Recueil 1997, 130, 879 et seq.; Bolm et al., Angew. Chem. 1997, 109, 773 et seq.; Bolm et al. Eur. J. Org. Chem. 1998, 21 et seq.; Baystone et al. in Speciality Chemicals 224 et seq.; Salvadori et al., Tetrahedron: Asymmetry 1998, 9, 1479; Wandrey et al., Tetrahedron: Asymmetry 1997, 8, 1529 et seq.; ibid. 1997, 8, 1975 et seq.; Togni et al. J. Am. Chem. Soc. 1998, 120, 10274 et seq., Salvadori et al., Tetrahedron Lett. 1996, 37, 3375 et seq.; WO 98/22415; and in particular DE 19910691.6, the relevant contents of each of which are hereby incorporated by reference.
Preferred molecular weight-enlarging polymers for binding the ligands are polyacrylates, polyvinylpyrrolidinones, polysiloxanes, polybutadienes, polyisoprenes, polyalkanes, polystyrenes, polyoxazolines or polyethers (PEG, PEP) or mixtures thereof. For the purposes of the present invention, mixtures are taken to mean the fact that individual monomers or polymers of differing origin are polymerised together to yield block copolymers, graft copolymers, random copolymers or even intimate mixtures of two or more polymers (i.e. polymer blends).
Polyacrylates, polystyrenes, polysiloxanes, polyethers and mixtures thereof are particularly preferred for this purpose.
The following structures are extremely preferred, wherein, on a statistical average, the values for a should be 1 and for b 10-30, preferably 20 (scheme 1). 
The molecular weight-enlarging polymers preferably exhibit an average molecular weight in the range from 5,000-500,000, particularly preferably from 5,000-300,000 g/mol. The present invention also provides a process for the production of a ligand according to the present invention, wherein the process comprises one of the following steps A)-C):
A) binding a ligand having a catalytically active center to a monomer directly or through a linker to provide a ligand modified monomer, then polymerizing said ligand modified monomer in the presence of one or more unmodified monomers;
B) binding a ligand having a catalytically active center to a polymer, either directly or through a linker;
C) following either step A) or B) and further copolymerizing the resulting polymer with one or more additional polymers, wherein said one or more additional polymers optionally comprise one or more catalytically active centers.
The ligand according to the present invention is preferably used for the production of enantiomerically enriched organic compounds. In particular, the present invention further provides a method for the selective production of enantiomerically enriched organic compounds (an enantioselective reaction that generates one enantiomer of a compound selectively over the opposite enantiomer), comprising performing a reaction on a starting material having a non-chiral site, such as a double bond, within the starting material to convert said non-chiral site into a chiral site, wherein said reaction is performed in the presence of a catalyst for said reaction, wherein the catalyst comprises a metal having thereon one or more molecular weight enlarged, homogeneously soluble ligands comprising a molecular weight enlarging polymer and one or more ligands, wherein said one or more ligands are homochiral active centers of bis(3,4-diarylphosphinyl)pyrrolidine, wherein said one or more ligands are bound to said molecular weight enlarging polymer via a linker selected from the group consisting of formulae a)-g)
wherein
R represents H, (C1-C8) alkyl, (C6-C18) aryl, (C7-C19) aralkyl, or ((C1-C8) alkyl)1-3-(C6-C18) aryl;
X represents (C6-C18) arylene, (C1-C8) alkylene, (C1-C8) alkenylene, ((C1-C8) alkyl)1-3-(C6-C18) arylene, or (C7-C19) aralkylene;
Z represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein Z is further bound directly to said molecular weight enlarging polymer; and
W represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein W is further bound directly to said ligand;
or said one or more ligands are bound directly to said molecular weight-enlarging polymer.
The use thereof in a membrane reactor is particularly preferred. As a result, syntheses normally performed in batch processes may proceed semi-continuously or continuously, which, from a cost standpoint, is particularly advantageous for an industrial process. The ligand according to the present invention, or the catalyst produced therefrom, is used in the membrane reactor in an analogous manner to the process described in DE 199 10 691.6; or Wandrey et al., Tetrahedron Asymmetry 1999, 10, 923-928, the contents of which are incorporated herein by reference.
The hydrogen required for hydrogenation may be supplied to the reactor as a gas. In this case, a semi-continuous processing method is suitable, in which, after hydrogenation in the reactor, the low molecular weight substances are separated and then a new feed batch is introduced and subsequently hydrogenated.
In the case of transfer hydrogenation, however, a continuous processing method is preferred, such as that described in xe2x80x9cAsymmetric transfer hydrogenation of Cxe2x95x90O and Cxe2x95x90N bondsxe2x80x9d, M. Wills et al. Tetrahedron: Asymmetry 1999, 10, 2045; xe2x80x9cAsymmetric transfer hydrogenation catalysed by chiral ruthenium complexesxe2x80x9d, R. Noyori et al. Acc. Chem. Res. 1997, 30, 97; xe2x80x9cAsymmetric catalysis in organic synthesisxe2x80x9d, R. Noyori, John Wiley and Sons, New York, 1994, S.123; xe2x80x9cTransition metals for organic Synthesisxe2x80x9d, eds. M. Beller, C. Bolm, Wiley-VCH, Weinheim, 1998, vol. 2, p. 97; and xe2x80x9cComprehensive Asymmetric Catalysisxe2x80x9d, eds.: Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Springer-Verlag, 1999, the relevant portions of each of which are hereby incorporated by reference. The membrane reactor may here act as a crossflow or dead end filtration module (DE 19947505.9 and DE 19910691.6 or xe2x80x9cEngineering processes for Bioseparationsxe2x80x9d, edited by: Laurence R. Weatherley, pages 135-165; Butterworth-Heinemann, 1994; ISBN: 0 7506 1936 8).
The ligand of the present invention provides a catalyst useful for hydrogenation of compounds containing double bonds, preferably Cxe2x95x90C, Cxe2x95x90N or Cxe2x95x90O double bonds, particularly for selective asymmetric hydrogenation of such compounds.
The present invention also provides a molecular weight-enlarged catalyst comprising a metal or metal ion and one or more molecular weight enlarged ligands, wherein the one or more molecular weight enlarged ligands comprise a molecular weight enlarging polymer and one or more ligands, wherein said one or more ligands are homochiral active centers of bis(3,4-diarylphosphinyl)pyrrolidine, wherein said one or more ligands are bound to said molecular weight enlarging polymer via a linker selected from the group consisting of formulae a)-g)
wherein
R represents H, (C1-C8) alkyl, (C6-C18) aryl, (C7-C19) aralkyl, or ((C1-C8) alkyl)1-3-(C6-C18) aryl;
X represents (C6-C18) arylene, (C1-C8) alkylene, (C1-C8) alkenylene, ((C1-C8) alkyl)1-3-(C6-C18) arylene, or (C7-C19) aralkylene;
Z represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein Z is further bound directly to said molecular weight enlarging polymer; and
W represents C(xe2x95x90O)Oxe2x80x94, C(xe2x95x90O)NHxe2x80x94, C(xe2x95x90O)xe2x80x94, NR, O, CHR, CH2, Cxe2x95x90S, S, PR, wherein W is further bound directly to said ligand;
or said one or more ligands are bound directly to said molecular weight-enlarging polymer. In particular, the molecular weight-enlarged catalyst is synthesised from a ligand according to the present invention and a metal or metal ion preferably selected from the group consisting of Ru, Rh, Ir, Pd, Ni, Pt.
Various strategies may be used to synthesize the ligand according to the present invention [such as methods a), b), or c) described above]. How the described linker/active center is bound to the pyrrolidine is left to the discretion of the person skilled in the art, but is preferably achieved by way of the nitrogen function thereof. How the linker/active center is bound to the polymer or monomer is also left to the discretion of the person skilled in the art, but a functionality present on the polymer or monomer is likewise preferably used in this case too. Reactions for achieving this coupling/binding reaction are known to the person skilled in the art.
The basic principle applies that the number of linkers/active centers per monomer in the polymer is as high as possible, such that the conversion rate per mole of polymer is consequently increased. On the other hand, however, the centers should be spaced apart in such a manner that any mutual negative influence on reactivity (TOF, selectivity) is minimized or does not occur. The spacing between linkers/active centers in the polymer should thus preferably be in the range from 5-50 monomer units, preferably 10-25 monomer units.
The site(s) on the polymer or on the monomer to be polymerised which are used for binding the linker/active center are those which may readily be functionalised or permit an existing functionality to be used for binding. Heteroatoms or unsaturated carbon atoms are thus preferably suitable for binding the components.
For example, in the case of styrene/polystyrene, the aromatic rings which are present may be used as attachment points to the linkers/active centers. Functionalities may readily be linked to these aromatic rings, preferably in positions 3, 4, 5, particular preferably in position 4, by means of standard aromatic chemistry, such as electrophilic aromatic acylation or electrophilic aromatic substitution, optionally followed by further functionalization by conventional organic chemistry methods. It is, however, also advantageous to incorporate an already functionalised monomer into the mixture to be polymerised and, after polymerisation, to bind the linker to the functionalities present in the polystyrene. Compounds which are advantageously suitable for this purpose include, for example, para-hydroxy- or para-aminostyrene derivatives.
In the case of polyethers, the existing terminal OH group is suitable for binding to the linkers/active centers by ester or ether formation or by oxidation of this group to form an acid group with subsequent esterification or amide formation (Nagel et al, Chem. Ber. 1986, 119, 3326-3343 hereby incorporated by reference).
In the case of polyacrylates, an acid group or ester group is in each case present in the monomer constituent, to which the linker or the active center may be bound through an ester or amide bond before or after polymerisation.
Polysiloxanes as a molecular weight enlarging polymer are preferably synthesised such that there are intermittent silylene groups modified by alkyl residues comprising double bonds or heteroatoms. The linkers/active centers may then be coupled to these sites.
They may preferably be bound to the functionalities under consideration in the polymer under hydrosilylation conditions (review of the hydrosilylation reaction by Ojima in The Chemistry of Organic Silicon Compounds, 1989 John Wiley and Sons Ltd., 1480-1526 hereby incorporated by reference).
Suitable polysiloxanes modified in this manner are known from the literature (xe2x80x9cSiloxane polymers and copolymersxe2x80x9d White et al., in S. Patai (ed.), xe2x80x9cThe Chemistry of Organic Silicon Compoundsxe2x80x9d, Wiley, Chichester, 1989, 46, 2954; C. Wandrey et al. TH:Asymmetry 1997, 8, 1975, relevant portions of these are incorporated by reference).
The purpose of the linker is to provide a space between the active center and the polymer in order to mitigate or eliminate any mutual interactions which are disadvantageous to the reaction. Scheme 2 below provides a suitable overview of linker precursors which may be used to provide a linkage with the polymer/monomer and active center. 
Selection is made on the basis of the possibility of readily coupling the linker, on the one hand, to the active center and, on the other, to the polymer/monomer. Preferred linkers, however, are those such as, for example, 1,4xe2x80x2-biphenyl, 1,2-ethylene, 1,3-propylene, PEG (2-10), xcex1,xcfx89-siloxanylene or 1,4-phenylene and xcex1,xcfx89-1,4-bisethylenebenzene or linkers which are obtainable from siloxanes of the general formula I: 
These may be bound to any double bonds present in the polymers and suitable functional groups of the active centre under hydrosilylation conditions. Linkers based on amino acids or dicarboxylic acids are most preferred.
For the purposes of the present invention, active center means the monomeric ligand bis(3,4-diarylphosphinyl)pyrrolidines. The word aryl means in this connection (C6-C18) aryl groups and ((C1-C8) alkyl)1-3-(C6-C18) aryl groups.
(C1-C8) Alkyl should be taken to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, including all bond isomers. In this connection, a (C1-C8) alkoxy residue is a (C1-C8) alkyl residue, which is bound via an oxygen atom to the molecule concerned.
(C1-C8) alkenylene means a (C1-C8) alkylene, with the proviso that at least one double bond is present in the residue.
A (C6-C18) aryl residue is taken to mean an aromatic residue having 6 to 18 C atoms. These in particular include compounds such as phenyl, naphthyl, anthryl, phenanthryl, or biphenyl residues. This residue may be substituted with one or more groups such as (C1-C8) alkoxy, NR2, or (C1-C8) haloalkyl, such as CF3.
A (C7-C26) aralkyl residue is a (C6-C18) aryl residue bound to the molecule via a (C1-C8) alkyl residue.
A (C7-C26) aralkylene residue should be taken to mean a residue which is attached to the molecule, on the one hand, via the (C1-C8) alkyl residue and, on the other, via the (C6-C18) aryl residue.
For the purposes of the present invention, a membrane reactor is taken to mean any reaction vessel in which the catalyst is enclosed in a reactor, while low molecular weight substances are supplied to the reactor or are able to leave it. The membrane can be incorporated directly into the reaction chamber or can be installed in a separate filtration module, in which the reaction solution flows continuously or intermittently through the filtration module and the retentate is returned to the reactor. Suitable embodiments are described, inter alia, in WO98/22415 and in Wandrey et al. in Jahrbuch 1998, Verfahrenstechnik und Chemieingenieurwesen, VDI pp. 151 et seq.; Wandrey et al. in Applied Homogeneous Catalysis with Organometallic Compounds, Vol. 2, VCH 1996, pp. 832 et seq.; Kragl et al., Angew. Chem. 1996, 6, 684 et seq., the relevant portions of each of which are incorporated herein by reference.
Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.